As the world amasses experience with Covid-19 vaccines, something we should have known from the start is coming into sharp focus.
Vaccines that are injected into arm muscles aren’t likely to be able to protect our nasal passages from marauding SARS-CoV-2 viruses for very long, even if they are doing a terrific job protecting lungs from the virus. If we want vaccines that protect our upper respiratory tracts, we may need products that are administered in the nose — intranasal vaccines.
Can they be made? Probably. Will they do what we want them to do, if they are made? Possibly. Is there still room for this type of next-generation product, given the record number of Covid vaccines that have already been put into use? Potentially. Will it be difficult to get them through development? Likely.
Some immunology basics would be helpful to understand the issues at stake here.
SARS-2 attacks us via the respiratory tract, with the resulting infections causing no symptoms in some people, mild to moderate cold and flu-like symptoms in others, and severe, life-threatening illness in the lungs of others.
Vaccines that are injected into the arm have done a spectacular job at preventing severe disease and death. But they do not generate the kind of protection in the nasal passages that would be needed to block all infection. That’s called “sterilizing immunity.”
There’s no reason to believe that intranasal vaccines would block all infection either, but experts say they could do a better job than existing vaccines, by better protecting mucus membranes of the nose and throat.
Florian Krammer, a vaccinologist at the Icahn School of Medicine at Mount Sinai Hospital, thinks existing vaccines likely induce high enough levels of circulating antibodies early after vaccination that some of them end up in the mucus membranes of the nose and throat. But as antibody levels start to drop in the months after vaccination, that early nasal protection seems to wane with it — especially in the face of the onslaught of the Delta variant, he suggested.
For disclosure purposes: Krammer’s colleague, veteran virologist Peter Palese, is developing an intranasal vaccine that recently completed a Phase 1 trial in Mexico. Krammer is involved in the project. But he sees potential in the broader effort to develop intranasal vaccines against Covid.
“There are some approaches that … look OK and I think they can be moved forward — if there’s funding,” he said. That’s a big “if,” he acknowledged, explaining that funding for next-generation Covid vaccines — innovations on the initial options — has dried up.
Other experts are unclear if intranasal vaccines are of high priority at this point in the pandemic.
“I think right now we’re still at the stage where we need to prevent just the basic disease. But I could imagine in the future sometime using that approach,” said Stanley Perlman, a coronavirus expert at the University of Iowa.
“I think that a mucosal immunity will help. I’m just concerned that these are really cold viruses, even though they cause pneumonia, and you’re never going to have sterilizing immunity,” he said.
The fact that the vaccines don’t block all infections and don’t prevent vaccinated people from transmitting isn’t a big surprise, said Kathryn Edwards, a vaccine expert at Vanderbilt School of Medicine. Years of experience with influenza vaccines — almost all of which are administered by intramuscular injection — have shown that route of delivery protects lungs, but not always the upper airways.
“We know that it works, but it’s certainly not perfect,” Edwards said.
Kanta Subbarao, an influenza expert who heads the WHO’s influenza collaborating center in Melbourne, Australia, agreed. “None of the current [Covid] vaccines are likely to provide robust protection in the upper respiratory tract. I think we would need something different for that,” she said.
Intranasal vaccines have multiple advantages. They don’t require syringes, cutting the expense of vaccination and the amount of medical waste an immunization program generates. A vaccine that can be puffed up a nostril probably doesn’t require a health care professional to administer it; the oral polio vaccine used in many developing countries is dripped into the mouths of children by trained volunteers.
And intranasal vaccines are — in theory, anyway — easier to administer to children and people who have a phobia of needles. That said, Kate O’Brien of the World Health Organization said in her experience as a pediatrician, children are not necessarily much more willing to take the nasally administered flu shot, FluMist, than a jab. “It doesn’t solve the delivery issues,” said O’Brien, the agency’s director of immunization, vaccination, and biologics.
There are challenges to making vaccines that are administered this way. Research on intranasal vaccines that don’t use live viruses to trigger immune responses — inactivated vaccines — have over the years produced disappointing results, Edwards said.
And it’s not yet clear if the mRNA vaccines that have been so important in the pandemic could be reformulated to be delivered intranasally.
“It may be possible but would take a lot of work and may require some new innovations,” Barney Graham, who led the team at the National Institute of Allergy and Infectious Diseases that designed the Moderna vaccine, said in an email. “Delivery to the respiratory tract is complicated by the mucociliary blanket that covers the [upper] airways. There are other groups working on it.”
An intranasally administered mRNA vaccine isn’t likely to emerge soon, Krammer said, suggesting it might be a “next, next, next-gen vaccine.”
Several intranasal vaccines are in development, in the U.S. and elsewhere. But one project was recently shelved after Altimmune, a biotech based in Gaithersburg, Md., saw disappointing results in its candidate vaccine.
One of the challenges of intranasal administration, at least for vaccines that use modified live viruses to trigger an immune response in the nasal passages, is they need to strike a delicate balance. The vaccines must deliver enough antigen — the immune response trigger — to effectively start an infection in the nose. That awakens the immune system to the existence of an invader it needs to protect against. The vaccines are designed so that the infection does not progress to illness. But too much of a dose, and the vaccine could trigger disease or unpleasant side effects, Subbarao said.
FluMist, which is marketed by AstraZeneca, had to be reformulated several years ago because U.S. data suggested it was no longer protecting children. And the vaccine has never been approved for use in older adults, whose years of exposure to flu viruses interfere with the vaccine’s ability to trigger that infection in the nose. At the other end of the spectrum, an intranasal flu vaccine developed by Berna Biotech and licensed in Switzerland was pulled from the market after it was seen to cause Bell’s palsy, a temporary facial paralysis, in some recipients.
AstraZeneca is working on an intranasal version of the vaccine it developed with the University of Oxford. A recently published animal study of the experimental vaccine at NIAID’s Rocky Mountain Laboratories in Hamilton, Mont., showed that hamsters vaccinated with the intranasal vaccine and then experimentally infected with SARS-2 had less virus in their nasal passages than exposed hamsters that hadn’t been vaccinated. Importantly, the vaccines still protected the animals’ lungs.
Vincent Munster, who led that work, said if the goal of Covid vaccination becomes trying to block transmission of the virus, intranasal vaccination could help. “The whole idea, of course, is that it works better at the place where it matters,” he said.
Would vaccines administered this way produce protection that is as long-lasting — durable in the lexicon of the vaccine world — as those the Covid vaccines we currently have? Munster said answering that question would require human trials. “I think it would be as durable. But you really need to have side-by-side data.”
Some vaccine researchers aren’t sure that when it comes to the work of developing intranasal vaccines, the juice is worth the squeeze. Many virologists believe that over time, as people’s immune systems develop experience with SARS-2 — either through vaccination or infection — the virus and humans will reach a détente with SARS-2, becoming like the four human coronaviruses, one of the causes of the common cold. “If this really is a cold virus, more than a flu-like virus, we may not care,” Perlman said.
Krammer, though, thinks there’s a role for the vaccines now. The one Mount Sinai is developing is produced in eggs — a low-tech, inexpensive production approach that could easily be adopted in low- and middle-income countries that don’t have the capacity to produce the more high-tech mRNA vaccines.
For her part, the WHO’s O’Brien seems to be reserving judgment on whether intranasal Covid vaccines will gain us much ground in the battle against SARS-2.
“Are they more durable? Do they actually have a different course of action? Are there ways of using them so that they’re better vaccines? Super supportive of that, but I don’t think it’s a no-brainer that if we only had nasal vaccines, you know, something would all be solved,” she said.